Our team pioneered the concepts of oral signal transduction therapy and disease stabilization endpoints. We have expanded our approach to signal transduction therapy combinations and we have added microproteomic techniques for illustration of drug mechanism in serially obtained tumor samples. Our driving hypothesis is that combinations focusing on signaling steps in series or in parallel and in multiple cell lineages within the microenvironment will yield improved outcomes. Aim 1) Advance our focus on molecular signaling inhibitors on the microenvironment in ovarian cancer. Our first success was the ability to demonstrate insufficiency of EGFR inhibitors in OvCa despite clear on-target activity. Further, we showed why vandetanib was not active by showing lack of on-target activity against VEGFR2. The combination of sorafenib and bevacizumab was a successful phase I and proof-of-mechanism trial. The OvCa phase II trial has shown activity in bevacizumab-nave women but less activity in those with prior exposure to bevacizumab, a critical finding given the toxicity and cost of bevacizumab;serial biopsies, imaging, and blood samples will be examined in the coming fiscal year. A new preclinical program has been initiated by a senior medical oncology fellow in the laboratory in order to predict targeted therapy combinations for clinical trials. This is discussed further in the project on angiogenesis and the microenvironment. Our in vitro findings of anti-angiogenic and anti-invasive activity of asparaginase led an investigator-initiated phase II study of pegaspargase in OvCa. 2) Cross-mining our translational data. We reported that high progranulin concentrations in early post-remission patient plasma prognosticated early OvCa recurrence (p&lt;0.0001). Two validation studies in serum (one in endometrial cancer) have been initiated;confirmatory data in serum will be preliminary data required for access to Gynecologic Oncology Group samples with clinical outcome (protocol pending). In addition, our Gynecologic Oncology Group study collecting serum from women undergoing surgical diagnosis of a pelvic mass has completed its accrual of over 2000 patients and is awaiting sample release;this will be examined collaboratively with our DOD/WHIRC colleagues. We are also investigating the value, toxicity, and site information from our experience with serial biopsies from our clinical trials. This information is important to show the value, utility, and safety of this translational approach. 3) Initiate program in HRD womens cancers. Treatments for BRCA1/2 mutation associated womens cancers is a critical unmet need. Our group is now a recognized center focusing on the treatment of women with BRCA1/2 mutation and BRCA-like womens cancers, now recognized as homologous recombination deficient cancers. We have completed accrual on the mutation carrier cohort of our phase I study of the PARP inhibitor olaparib in combination with carboplatin and are initiating examination of expansion cohort patient serial biopsies and blood samples in collaboration with CCR colleagues;expansion cohorts are accruing in TNBC and high grade serous OvCa. We have initiated examination of sequence specificity of carboplatin and olaparib in vitro and in a new clinical trial open to all womens cancers. The senior fellow overseeing this work was recognized with the Jane C. Wright ASCO Young Investigator Award to support a postbaccalaureate fellow for the project. The trial will examine the effects of sequencing the agents on DNA damage and repair. Laboratory studies are investigating potential mechanisms underlying the cooperative interaction of these agents as a collaboration with numerous CCR colleagues. 4. Examine other applications of HRD drug combinations. Our previous preclinical data indicated an interactive effect of PARP inhibition with angiogenesis inhibition, in a sequence-specific fashion. Preclinical studies are ongoing to further understand this. We have recently revised our clinical plans for the combination in response to recent data from Matulonis and colleagues at the Dana Farber Cancer Center indicating clinical activity and safety of the combination of olaparib and cediranib. We incorporated a translational endpoint plan into the CTEP-approved randomized phase II trial of olaparib v. olaparib + cediranib for women with high grade serous and endometrioid OvCa, where all participating patients are to be seen in our clinic for sample acquisition and imaging pretherapy and on day 3;we will also be a treatment site on the trial. IRB approval is pending. Endpoints will include biopsies for HRD and angiogenesis endpoints, DCE-MRI for tissue vascular flow changes, and blood samples for circulating endothelial cell precursors, pharmacogenomics, and circulating cytokine concentrations. Biopsies will also be requested of mutation carriers at the time of progression of disease in order to further examine the issue of secondary HR enabling mutations. This trial is a collaborative study with leading groups in the HRD treatment field and a high impact, high priority trial.